Molecular Docking Analysis of Triazole Analogues as Inhibitors of Human Neutrophil Elastase (HNE), Matrix Metalloproteinase (MMP 2 and MMP 9) and Tyrosinase

 

V. Vijayakumar¹, N. Radhakrishnan²*, P. Vasantha-Srinivasan³

¹Department of Chemistry, Anna University, Chennai-25, Tamil Nadu, India.

^2,3Department of Biochemistry, St. Peter’s Institute Higher Education and Research, Avadi, Chennai,

Tamil Nadu, India.

 

ABSTRACT:

Triazole analogues are well known to have desirable properties for medicinal chemistry such as hydrogen bonding capability, moderate dipole character, rigidity and stability under in vivo conditions etc. This prompts us to carry out the present study, we have selected 20 triazole analogues and evaluated on the docking behavior of four targeted enzymes such as HNE, MMP 2, MMP 9 and tyrosinase. The molecular physicochemical analysis revealed that all the tested ligands (expect ligand 5 and 18) showed nil violation and complied well with the Lipinski’s rule of five. ADME analysis showed that ligand 15 alone predicated to have low gastrointestinal (GI) absorption effect. Docking studies revealed that ligand 18 [2-(2,4-difluorophenyl)-1-(4-((1-(4-ethylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol] had exhibited the maximum binding energy for three target enzymes such as HNE, MMP 2 and MMP 9. The present study has paved a new insight in understanding 20 triazole analogues as potential inhibitors against HNE, MMP 2, MMP 9 and tyrosinase.

 

 

INTRODUCTION:

Triazole analogues are five member heterocyclic compounds basically having two carbon and three nitrogen atoms in their structure. Triazole analogues have been reported to posses various biological activities such as analgesic, analeptic, anti-anxiety, anti-cancer, anti-convulsant, anti-depressant, anti-fungal, anti-histaminic, anti-inflammatory, anti-hypertensive, anti-malarial, anti-microbial, anti-oxidants, anti-tubercular and anti-viral etc¹.

 

Moreover, some commercial available drugs like Alprazolam (anti-anxiety drug), Anastrozole (breast cancer), Etizolam (anti-anxiety), Fluconazole (anti-fungal), Intraconazole (anti-fungal), Letrozole (breast cancer), Ribavirin (anti-viral), Rizatriptan (anti-migraine), Rufinamide (anti-convulsant), Triazolam and Voriconazole (anti-fungal) are known to have triazole moiety². Apart from these, triazole analogues have been reported to posses unique advantages like i) potent pharmacological activities, ii) no or low adverse effects, iii) more bioavailability, iv) poor drug resistances and v) better pharmacokinetics property etc.¹.

 

Molecular docking is one of the bioinformatics tools to study the interaction between the small molecules (ligands) and protein/enzyme (receptor), predict the binding site of the ligand. Previously, researchers had reported the molecular docking studies of (2E)-N-Hydroxy-3-[3-(Phenylsulfamoyl) Phenyl] prop-2-Enamide (Belinostat) against Ebola virus glycoprotein and 1, 2, 4-triazin analogue of diclofenac as potential ligand for Parkinson’s disease^2-3. Panigrah and co-workers had reported the synthesis, antimicrobial activity and molecular docking studies of novel oxazolidinone-thiophene chalcone hybried derivatives⁴. Chelamalla and Makula reported the molecular docking and ADMET analysis of pyrimidine coumarin scaffolds⁵. Hasan and coworkers had reported the molecular docking investigations of 3, 5, 7-trihydroxy-6,7-dimethoxy flavone⁶. Ramjith and Shahim had reported the molecular docking studies of novel imidazo[2,1-b]-1,3,4 thiadiazole derivatives⁷.  Similarly, few other organic compounds have been reported to possess biological activity both in vitro and in vivo studies^8-10.

 

Kumar and co-workers has reported anti-inflammatory activity for 28 (1, 2, 4)-triazole derivatives, among which triazole derivative 17 (n-butyl group at position 4) had shown better in vivo anti-inflammatory activity¹¹. Similarly, Wuest and   co-workers has reported that diaryl substituted 1, 2, 3 triazole derivatives have exhibited good cyclooxygenase (COX-2) inhibition activity¹². This prompts us to carry out the present study, we have selected 20 triazole analogues they are (1) 4H-1,2,4-triazole; (2) 4-butyl-4H-1,2,4-triazole; (3) 4-octyl-4H-1,2,4-triazole; (4) 4-(4H-1,2,4-triazol-4-yl)butan-1-amine; (5) 4-octyl-3,5-dipropyl-4H-1,2,4-triazole; (6) 4-amino-5-ethyl-4H-1,2,4-triazole-3-thiol; (7) 3-ethyl-5,6-dihydro-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-one; (8) 5-methyl-4-phenyl-4H-1,2,4-triazole-3-thiol; (9) (E)-2-(((3-(p-tolyloxy)-4H-1,2,4-triazol-4-yl)imino)methyl)phenol; (10) 2-(4-acetylphenyl)-5-methyl-2H-1,2,3-triazole-4-carboxylic acid; (11) 5-azido-4H-1,2,4-triazol-3-amine; (12) 2-(2,4-difluorophenyl)-1,3-di(4H-1,2,4-triazol-4-yl)propan-2-ol; (13) 4-(2-(2,4-dimethylphenyl)-2-methyl-3-(1-nitro-1,5-dihydro-4H-1,2,4-triazol-4-yl)propyl)-4H-1,2,4-triazole; (14) 6-((R)-3-aminopiperidin-1-yl)-3-((1-methyl-4,5-dihydro-1H-1,2,3-triazol-4-yl)methyl)-1-(prop-1-yn-1-yl)dihydropyrimidine-2,4(1H,3H)-dione; (15) (2-(4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-2H-1,2,3-triazol-2-yl)ethyl)phosphonic acid; (16) (2R,3S,4R,5R)-2-(hydroxymethyl)-5-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)tetrahydrofuran-3,4-diol; (17) 1-(1-(2,4-dichlorophenyl)-2-(1H-1,2,3-triazol-1-yl)ethyl)-4-ethyl-5-methyl-1H-1,2,3-triazole; (18) 2-(2,4-difluorophenyl)-1-(4-((1-(4-ethylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; (19) 4-((2R)-3-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)pyrimidine; (20) 4-(2-((2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)-2,3-dihydrothiazol-4-yl)benzonitrile, were evaluated on the docking behavior of Human neutrophil elastase (HNE), matrix metalloproteinase (MMP 2 and MMP 9) and tyrosinase. The results shows that the potential of triazolium analogues as human neutrophil elastase (HNE), matrix metalloproteinase (MMP 2 and MMP 9) and tyrosinase inhibitors.

 

MATERIALS AND METHODS:

Ligand preparation:

Chemical structures of 20 ligands (triazole analogues) were drawn in Chem Bio Draw Ultra 12.0 and energy minimization of ligands was carried out by Chem Bio 3D Ultra 12.0, according to the reported procedure¹³. These structures were employed for further Patch Dock.

 

Target protein identification and preparation:

The three dimensional (3D) structures of the HNE (PDB ID: 1H1B with resolution of 2.00 A) and MMP 2 (PDB ID: 1QIB with resolution of 2.80 A), MMP 9 (PDB ID: 4H1Q with resolution of 1.59 A) and Tyrosinase (PDB ID: 2Y9W with resolution of 2.30 A) were obtained from the Research Collaborator for Structural Bioinformatics (RCSB) Protein Data Bank (www.rcsb.org)^13-14. A chain of these proteins was processed individually by removing another chain (B, C and D), ligands in addition to the crystallographically observed water particles (water without hydrogen bonds). The protein mentioned above was prepared using UCSF Chimera software (www.cgi.ucsf.edu/chimera).

 

ADME analysis:

ADME (Absorption, Distribution, Metabolism and Excretion) analysis was performed by Swiss ADME analysis was carried by a standard default protocol¹⁵.

 

Docking studies:

Docking studies were carried out by the PatchDock online server (http://bioinfo3d.cs.tau.ac.il/PatchDock). PatchDock adopts geometry-based molecular docking algorithm method was used to recognize the binding scores, by binding residues atomic contact energy of the given ligands. The docking results were obtained through the email address. We also use to get uniform resource locator (URL) which provides the top 20 solutions in a table form via email. From these, the top one solutions (the docked protein-ligand complex) was selected and downloaded in a database (pdb) file format. Further, the binding site analysis was carried out by PyMOL software (www.pymol.org)¹⁶.

 

RESULTS AND DISCUSSIONS:

Twenty triazole analogues have been selected for the present study, as shown in the Table 1.

 

Table 1: Represents the International Union of Pure and Applied Chemistry (IUPAC) name and Simplified Molecular Input Line Entry System (SMILES) of 20 triazole analogues.

 

Table 2: Molecular physicochemical descriptors analysis of 20 triazole analogues using Molinspiration online software tool.

^aOctanol-Water partition coefficient, ^b Polar surface area,  ^cNumber of non-hydrogen atoms,^d Molecular weight, ^e Number of hydrogen bond acceptors [ O and N atoms], ^f Number of hydrogen bond donors [ OH and NH groups], ^g Number of Rule of 5 violations, ^h Number of rotatable bonds, ⁱ Molecular volume.

With regard to drug-likeness score, if the score is > 0 is active, -5.0 to -0.0 is moderate active and < -5.0 is inactive¹⁸.

 

It could be beneficial to know the physiochemical, drug-likeness and ADME (Absorption, Distribution, Metabolism and Excretion) properties of these 20 ligands before carry out docking studies. Lipinski’s rule of five was applied to know the above said properties and violation of the Lipinski’s rule of five is when logA>5, MW >500, number of N, O (hydrogen bond receptor) >10, number of OH and NH (hydrogen bond donor) >5 and number of the rotatable bond (rotb) >15¹⁷. In the present study, all the ligands (expect ligand 5 and 18) showed nil violation and complied well with the Lipinski’s rule of five as shown in Table 2.

All the ligands showed active to moderate active score towards all the six descriptions. Interestingly, none of them showed inactive score as shown in Table 3.

 

Table 3: Drug-likeness property analysis of 20 triazole analogues using Molinspiration tool.

*GPCR- G Protein-coupled receptors

 

Table 4: ADME analysis of 20 triazole analogues using Swiss ADME online tool.

^●-Gastrointestinal, ^#-Blood-brain barrier permeant, ^□-P-gp-P-glycoprotein substrate, ^*-CYP-Cytochrome P450 Inhibitors, ^◊-Skin Permeation (cm/s).

 

Absorption, Distribution, Metabolism and Excretion (ADME) is essential analysis tool and which is commonly accepted in the early stage of drug discovery, drug design and drug screening, owing to its unique characteristic nature^19,20. Table 4 showed the ADME profile of the selected 20 triazole analogues; all the ligands are predicted to have high gastrointestinal (GI) absorption effect except ligand 15 [(2-(4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-2H-1,2,3-triazol-2-yl)ethyl)phosphonic acid].

 

Human nucleophil elastase (HNE) is a key enzyme which plays major role in degenerative and inflammatory diseases, through proteolysis extracellular matrix (ECM) components^21-24. The docking studies and binding site analyses in Table 5, shows that ligand 18 [2-(2,4-difluorophenyl)-1-(4-((1-(4-ethylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol] with the highest ACE [atomic contact energy (-330.87 kcal/mol)] while ligand 4 [4-(4H-1,2,4-triazol-4-yl)butan-1-amine] showed the least ACE (-79.11 kcal/mol) with that of HNE.

Table 5: The interaction energy analysis of 20 triazole analogues with Human nucleophil elastase (HNE) using PatchDock.

 

The present finding was in good agreement with earlier report, where compound 3b [(N,N’,N,N’)-N,N’-(4,4’-(butane-1,4-diylbis(oxy))bis(4,1-phenylene)bis(methan-1-yl-1-ylidene)bis (3,5- diethyl-4H-1,2,4-triazol-4-amine)] exhibited potent elastase inhibitory activity²⁵. In the present study, interaction with Ser 195 amino acid residue has been shown by five ligands such as ligand 3, 14, 17, 18 and 19.  Similarly, interaction with His 57 amino acid residue has been shown by three ligands such as ligand 6, 9, and 13. Previously Vergellia et al reported that Ser 195 amino acid present in the active site, (responsible for the nucleophilic attack) and similarly His 57 amino acid present in the catalytic site (in all the serine proteases)²⁶.

 

Matrix metalloproteinase’s (MMPs) are family of zinc-dependent endopeptidases regulates both development and physiological events. There are now more than 20 members of the MMP family among them, MMP 2 (Gelatinase A) and MMP 9 (Gelatinase B) have been reported to be elevated in the pathological conditions like as aging, cancer, inflammation and wound healing²¹.  The docking studies and binding site analyses in Table 6, shows that ligand 18 [2-(2,4-difluorophenyl)-1-(4-((1-(4-ethylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol] with the highest ACE [atomic contact energy (-490.13 kcal/mol)] while ligand 1 [4H-1,2,4-triazole] showed the least ACE (-49.60 kcal/mol) with that of MMP 2. Similarly in the case of MMP 9, Table 7 shows that ligand 18 [2-(2,4-difluorophenyl)-1-(4-((1-(4-ethylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol] with the highest ACE [atomic contact energy (-489.56 kcal/mol)] while ligand 1 [4H-1,2,4-triazole] showed the least ACE (-112.43 kcal/mol) with that of MMP 9.

 

Table 6: The interaction energy analysis of 20 triazole analogues with MMP 2 using PatchDock

 

Table 7:  The interaction energy analysis of 20 triazole analogues with MMP 9 using PatchDock.

 

Triazole derivatives containing thiirane compound reported to exhibit strong gelatinase inhibitory activity²⁸. In the present study, interaction with Leu 188 amino acid residue has been shown by two ligands such as ligand 18 [2-(2,4-difluorophenyl)-1-(4-((1-(4-ethylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol] and ligand 20 [4-(2-((2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)-2,3-dihydrothiazol-4-yl)benzonitrile]. The present finding was in good agreement with earlier report²¹.

 

Tyrosinase is the main regulatory enzyme in melanogenesis pathway that too mainly in the primary two stages such as (i) tyrosine hydroxylation to 3, 4-dihydroxyphenylalanine (DOPA) and (ii) the oxidation of DOPA to dopoquinone²³.  The docking studies and binding site analyses in Table 8, shows that ligand 10 [2-(4-acetylphenyl)-5-methyl-2H-1, 2, 3-triazole-4-carboxylic acid] with the highest ACE [atomic contact energy (-152.56 kcal/mol)]. While four ligands such as ligand 12 [2-(2,4-difluorophenyl)-1,3-di(4H-1,2,4-triazol-4-yl)propan-2-ol], ligand 16 [(2R,3S,4R,5R)-2-(hydroxymethyl)-5-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)tetrahydrofuran-3,4-diol], ligand 19 [4-((2R)-3-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)pyrimidine] and ligand 20 [[4-(2-((2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)-2,3-dihydrothiazol-4-yl)benzonitrile] showed poor binding phenomenon as reported by Akdogan and co-workers²⁹.

 

Table 8: The interaction energy analysis of 20 triazole analogues with tyrosinase inhibitors using PatchDock.

 

2,2’-(4,4’-(butane-1,4-,diyl) bis (3-methy1-5-oxo-1H-1,2,4-triazole-4,1(4H,5H)-diyl))bis(N’-(thiophen-2-ylmethylene)acetohydrazide and 2,2’-(4,4’-(hexane-1,6-,diyl) bis (3-methy1-5-oxo-1H-1,2,4-triazole-4,1(4H,5H)-diyl))bis(N’-(thiophen-2-ylmethylene)acetohydrazide have been reported to inhibit tyrosinase activity³⁰. Similarly, (Z)-3-(2-Fluorobenzyl)-4-[(4-fluorobenzylidene) amino]-1H-1, 2, 4-triazole-5(4H)-thione and (Z)-3-(2-Fluorobenzyl)-4-[(4-hydroxybenzylidene) amino]-1H-1, 2, 4-triazole-5(4H)-thione have been reported to exhibit strong tyrosinase inhibitory activity³¹. In the present study, interaction with Lys 379 amino acid residue has been shown by three ligands such as ligand 8 [5-methyl-4-phenyl-4H-1,2,4-triazole-3-thiol], ligand 15 [(2-(4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-2H-1,2,3-triazol-2-yl)ethyl)phosphonic acid] and ligand 17 [1-(1-(2,4-dichlorophenyl)-2-(1H-1,2,3-triazol-1-yl)ethyl)-4-ethyl-5-methyl-1H-1,2,3-triazole]. The present finding was in good agreement with earlier report²³.

 

CONCLUSION:

In the present study ligand 18 [2-(2,4-difluorophenyl)-1-(4-((1-(4-ethylbenzyl)-1H-1,2,3-triazol-4-yl)methyl) piperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl) propan-2-ol] had exhibited the maximum binding energy for three target enzymes such as HNE, MMP 2 and MMP 9, whereas in the case of tyrosinase ligand 10 [2-(4-acetylphenyl)-5-methyl-2H-1, 2, 3-triazole-4-carboxylic acid] had shown the maximum binding energy. In addition to this all the ligands (expect ligand 5 and 18) exhibited zero violation and complied very well with the Lipinski’s rule of five. And moreover, ADME analysis showed that all the ligands (expect ligand 15) predicated to have high gastrointestinal (GI) absorption effect. Hence, the present study has paved a new insight in understanding 20 triazole analogues as potential inhibitors against HNE, MMP 2, MMP 9 and tyrosinase.

 

ACKNOWLEDGEMENTS:

The author VV thankful to Department of Chemistry, Anna University, Chennai-25 and N.R would like to express his sincere gratitude to Department of Biochemistry, St. Peter’s Institute Higher Education and Research (Deemed to be University), Avadi, Chennai-54, Tamil Nadu, India for providing research facilities.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

REFERENCES:

1.      Asif M. A brief review on anti-tubercular activity of pharmacological activity of some triazole analogues. Global J Res and Rev. 2014; 1(3):051-058.

2.      Otuokere IE, Amaku FJ, Alisa CO. In silico geometry optimization, excited – state properties of (2E)-N-Hydroxy-3-[3-(Phenylsulfamoyl) Phenyl] prop-2-enamide (Belinostat) and its molecular docking studies with Ebola Virus glycoprotein. J Pharm Res 2015; 5(3):131-137.

3.      Sudhakar P, Pushkalai S, Poorana, Sabarinath C, Priyadharshini S, Haripriya S. Molecular docking and synthesis of 1, 2, 4 -triazin analogue of diclofenac as potential ligand for parkinson's. Res J Pharm  Pharmcodynamics 2018; 10(1):8-12.

4.      Panigrahi N, Ganguly S, Jagadeesh P. Synthesis, antimicrobial evaluation and molecular docking studies of novel Oxazolidinone-thiophene chalcone hybrid derivatives. A J Res and Tech 2018; 11(12):5611-5622.

5.      Chellamalla R, Makula A. Molecular docking studies and ADMET predictions of pyrimidine coumarin scaffolds as potential IDO inhibitors. A J Res Chem 2017; 10(3):331-340.

6.      Hasan T, Ghalib RM, Mehdi SH, Singh PK, Baqri SSR. Normal mode analysis, electronic parameters and molecular docking study of 3, 5, 4’-Trihydroxy-6, 7-dimethoxy-flavone (Eupalitin) using first principle. A J Res Chem 2017; 10(6):789-797.

7.      Ramjith US, Shahim M. Molecular docking study of novel imidazo-1, 3, 4 thiadiazole derivatives. Res J Pharm and Tech 2013; 6(6):688-694.

8.      Pavlo V, Zadorozhnii VV, Kiselev, AE, Titova, AV, Kharchenko, Ihor O. Pokotylo OV, Okhtina. Molecular docking studies of N-5-aryl-1, 3, 4-oxadiazolo-2, 2-dichloroacet-amidines as inhibitors of enoyl-ACP reductase Mycobacterium tuberculosis. Res J Pharm and Tech 2017; 10(4):1091-1097.

9.      Pavlo VZadorozhnii, Vadym VK, Nataliia OT, Aleksandr VK, Ihor OP, Oxana VO, Oxana VK. In Silico prediction and molecular docking studies of N-Amidoalkylated derivatives of 1, 3, 4-oxadiazole as COX-1 and COX-2 potential inhibitors. Res J Pharm and Tech 2017; 10(11):3957-3963.

10.   Godhani DR, Jogel AA, Sanghani AM, Mehta JP. Synthesis and biological screening of 1, 2, 4-triazole derivatives. Ind J Chem. 2015; 54B:556-564.

11.   Kumar H, Javed SA, Khan SA, Amir M. 1, 3, 4-Oxadiazole/thiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid: Synthesis and preliminary evaluation of biological properties. Euro J Med Chem. 2008; 43:2688-2698.

12.   Wuest F, Tang X, Kniess T, Pietzsch J, Suresh M. Synthesis and cyclooxygenase inhibition of various (aryl-1,2,3-triazole-1-yl)-methanesulfonylphenyl derivatives. Bio Med Chem. 2009; 17:1146-1151.

13.   Vijayakumar V, Radhakrishnan N, Rameshkumar C. Molecular docking analysis of imidazole derivatives and polybenzimidazole analogues as inhibitors of superoxide dismutase (SOD) and Xanthine oxidase (XO). IEEE International Conference on Smart Technologies and Management for Computing, Communication, Controls, Energy and Materials (ICSTM) 2017; 513-516.

14.   Navjot Kaur, Monika, Kulwinder Singh. 3D-QSAR and Molecular Docking Studies of N-(2-Aminophenyl)-Benzamide Derivatives as Inhibitors of HDAC_2. Res J Pharm and Tech 2014; 7(7):760-770.

15.   Wang J, Urban L. The impact of early ADME profiling on drug discovery and development strategy. Drug Discovery World. 2004; 5:73-96.

16.   Hailu M, Narayanaswamy R, Abrehame S, Manoj VR. In silico analysis of Glycogen Synthase Kinase 3-Beta (GSK-3β) as aflatoxin binder. Biomed Pharmacol J 2019; 12(3):1449-1456.

17.   Lipinski CA, Lambardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001; 46:3-26.

18.   Singh S, Gupta AK, Verma A. Molecular properties and bioactivity score of the Aloe vera antioxidant compounds- In order to lead finding. Res J Pharm Biol Chem Sci. 2013; 4(2):876-891.

19.   Vijayakumar V, Radhakrishnan N, Rameshkumar C. Predicting the biodegradability  nature of imidazole and its derivatives by modelling two histidine degradation enzyme (Urocanase and Formiminoglutamase) activities. Asian J Pharm Clin Res. 2017; 10 (11):383-386.

20.   Wang J, Urban L. The impact of early ADME profiling on drug discovery and development strategy. Drug Discovery World. 2003; 5:73-96.

21.   Radhakrishnan N, Lam KW, Intan IS. In silico analysis of selected honey constituents as human neutrophil elastase (HNE) and matrix metalloproteinases (MMP 2 and 9) inhibitors. Int J Food Prop. 2015; 18:2155-2164.

22.   Radhakrishnan N, Lam KW, Faridah A, Intan IS. Molecular docking analysis of curcumin analogues elastase (HNE) inhibitors. Bangladesh J. Pharmacol. 2014; 9:77-82.

23.   Radhakrishnan N, Lam Kok Wai, Norhaizan Mohd Esa. Molecular docking analysis of phytic acid and 4-hydroxyisoleucins as cyclooxygenase-2, microsomal prostaglandin E synthase-2, tyrosinase, human neutrophil elastase, matrix metalloproteinase-2 and 9, xanthine oxidase, squalene synthase, nitric oxide synthase, human aldose reductase and lipoxygenase inhibitors. Pharmacogn Mag. 2017; 13 (51):S512-S518.

24.   Vijayakumar V, Prabakaran A, Radhakrishnan N, Muthu S, Rameshkumar C, Paulraj EI. Synthesis, characterization, spectroscopic studies, DFT and molecular docking analysis of N4, N4′-dibutyl-3, 3′-diaminobenzidine. J Mol Struct. 2019; 1179:325-335.

25.   Gumrukcuoglu N, Sokmen BB, Ugras S, Ugras HI, Yanardag R. Synthesis, antibacterial, antielastase, antiurease and antioxidane activities of new 1,4-butylene bridged bis-1,2,4-triazole derivatives. J Enzyme Inhib Med Chem. 2013; 28(1):89-94.

26.   Vergelli C, Schepetkin IA, Crocetti L, Lacovone A, Giovannoni MP, Guerrini G, Khlebnikov AI, Ciattini S, Ciciani G, Quinn MT. Isoxazol-5(2H)-one: a new scafford for potent heman neutrophil elastase (HNE) inhibitors. J Enzyme Inhib Med Chem. 2017; 32(1):821-831.

27.   Romanchikova N, Trapencieris P, Zemitis J, Turks M. A new matrix metalloproteinase-2 inhibitor triazolylmethyl aziridine reduces melanoma cell invasion, angiogenesis and tergets ERK1/2 phosphorylation. J Enzyme Inhib Med Chem. 2014; 29(6):765-772.

28.   Testero SA, Llarrull LI, Fisher JF, Chang M, Mobashey S. Exploring the functional space of thiiranes as gelatinase inhibitors using click chemistry. ARKIVOC 2011; 7:221-236.

29.   Akdogan ED, Erman B, Yelekci K. In silico design of novel and highly selective lysine‑specific histone demethylase inhibitors. Turk J Chem. 2011; 35:523‑42.

30.   Unver Y, Celik F, Dugdu E, Barut B, Sancak K. Synthesis of new bis-triazole compounds including Schiff bases and enzyme inhibition and antioxidant activities. J  Med Chem. 2016; 1(1): 005-010.

31.   Rafiq M, Saleem M, Hanif M, Kang SK, Seo SY, Lee KH. Synthesis, structural elucidation and bioevaluation of 4-amino-1, 2, 4-triazole-3-thione’s Schiff base derivatives. Arch Pharm Res. 2015. 

 

 

Accepted on 14.12.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(6): 2777-2783.